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Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial
Kim Margolin1, Marc S Ernstoff, Omid Hamid
1University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org
Background:
Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases.
Methods:
Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766.
Findings:
We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis.
Interpretation:
Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population.
Funding:
Bristol-Myers Squibb.
Insights
Ipilimumab shows activity in melanoma patients with brain metastases, especially when asymptomatic. The immunotherapy drug demonstrated no unexpected toxic effects in this patient group.
Area of Science:
- Oncology
- Immunotherapy
- Clinical Trials
Background:
- Brain metastases are common in advanced melanoma and a leading cause of death.
- Ipilimumab is an immunotherapy drug that has shown improved survival in advanced melanoma patients.
- Investigating ipilimumab's safety and efficacy in melanoma patients with brain metastases is crucial.
Purpose of the Study:
- To assess the safety and activity of ipilimumab in patients with melanoma and brain metastases.
- To evaluate disease control rates and adverse events in two distinct patient cohorts (asymptomatic vs. symptomatic with corticosteroids).
Main Methods:
- A clinical trial enrolled 72 melanoma patients with brain metastases across two parallel cohorts (A: asymptomatic, B: symptomatic).
- Patients received intravenous ipilimumab (10 mg/kg) every 3 weeks for four doses, with extended dosing for stable patients.
- Disease control (complete response, partial response, or stable disease) was assessed at 12 weeks using modified WHO criteria.
Main Results:
- Disease control after 12 weeks was observed in 18% of cohort A and 5% of cohort B patients.
- Disease control specifically within the brain was 24% in cohort A and 10% in cohort B.
- Common grade 3 adverse events included diarrhea and fatigue; one patient died from drug-related immune-related colitis.
Conclusions:
- Ipilimumab demonstrates activity in select patients with advanced melanoma and brain metastases.
- Efficacy appears higher in patients with small, asymptomatic brain metastases.
- Ipilimumab did not exhibit unexpected toxicity in this population.
